Deletion of both <i>p62</i> and <i>Nrf2</i> spontaneously results in the development of nonalcoholic steatohepatitis

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Author(s)

    • AKIYAMA Kentaro Akiyama Kentaro
    • Doctoral Programs in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan|Japan Society for the Promotion of Science, 5-3-1 Kojimachi, Chiyoda-ku, Tokyo 102-0083, Japan
    • WARABI Eiji Yamagata Kenji
    • Division of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
    • OKADA Kosuke Onizawa Kojiro
    • Division of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
    • KOSE Katsumi Shoda Junichi
    • Medical Sciences, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
    • ISHIGE Kazunori Okada Kosuke
    • Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
    • MIZOKAMI Yuji Yanagawa Toru
    • Division of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
    • YAMAGATA Kenji Ishii Tetsuro
    • Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
    • SHODA Junichi Mizokami Yuji
    • Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan

Abstract

<p>Nonalcoholic steatohepatitis (NASH) is one of the leading causes of chronic liver disease worldwide. However, details of pathogenetic mechanisms remain unknown. Deletion of both <i>p62/Sqstm1</i> and <i>Nrf2</i> genes spontaneously led to the development of NASH in mice fed a normal chow and was associated with liver tumorigenesis. The pathogenetic mechanism (s) underlying the NASH development was investigated in <i>p62:Nrf2</i> double-knockout (DKO) mice. DKO mice showed massive hepatomegaly and steatohepatitis with fat accumulation and had hyperphagia-induced obesity coupled with insulin resistance and adipokine imbalance. They also showed dysbiosis associated with an increased proportion of gram-negative bacteria species and an increased lipopolysaccharide (LPS) level in feces. Intestinal permeability was elevated in association with both epithelial damage and decreased expression levels of tight junction protein zona occludens-1, and thereby LPS levels were increased in serum. For Kupffer cells, the foreign body phagocytic capacity was decreased in magnetic resonance imaging, and the proportion of M1 cells was increased in DKO mice. <i>In vitro</i> experiments showed that the inflammatory response was accelerated in the <i>p62</i>:<i>Nrf2</i> double-deficient Kupffer cells when challenged with a low dose of LPS. Diet restriction improved the hepatic conditions of NASH in association with improved dysbiosis and decreased LPS levels. The results suggest that in DKO mice, activation of innate immunity by excessive LPS flux from the intestines, occurring both within and outside the liver, is central to the development of hepatic damage in the form of NASH.</p>

Journal

  • Experimental Animals

    Experimental Animals 67(2), 201-218, 2018

    Japanese Association for Laboratory Animal Science

Codes

  • NII Article ID (NAID)
    130006733609
  • NII NACSIS-CAT ID (NCID)
    AA11032321
  • Text Lang
    ENG
  • ISSN
    1341-1357
  • NDL Article ID
    028961675
  • NDL Call No.
    Z54-H752
  • Data Source
    NDL  J-STAGE 
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